MyD88 is essential for clearance of <i>Leishmania major</i>: possible role for lipophosphoglycan and Toll‐like receptor 2 signaling

Veer, Michael John de; Curtis, Joan M.; Baldwin, Tracey M.; DiDonato, Joseph A.; Sexton, Adrienne; McConville, Malcolm J.; Handman, Emanuela; Schofield, Louis

doi:10.1002/eji.200324128

Cited by 293 publications

(343 citation statements)

References 53 publications

(55 reference statements)

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“…The cytokines promotes an up-regulation of the TLR2 to maintain a continuous inflammatory response by unknown mechanism 9 . Our results are similar to those obtained in experimental models of L. major in mice 4,6,8 . Lipophosphoglycan, a polymer of repeating Galβ1-4Manα-PO 4 units and a prominent Leishmania surface glycoconjugate 14 , activates both mouse macrophages and human NK cells through TLR2 4,6 .…”

Section: Discussionsupporting

confidence: 91%

“…In our study, TLR2 was expressed only by macrophage in the double immunostaining. Macrophage is the most important cell in the cutaneous leishmaniasis and several studies demonstrated that TLR2 is expressed at the surface of this cell 6,8,12,13 . The absence of TLR2 in other cells can be associated with the phase of the disease, because DC and NK cells decrease in this period of the leishmaniasis.…”

Section: Discussionmentioning

confidence: 99%

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Expression of TLR2 and TLR4 in lesions of patients with tegumentary american leishmaniasis

Tuon

Fernandes

Duarte

et al. 2012

Rev. Inst. Med. trop. S. Paulo

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SUMMARYObjectives: The aim of this study was to describe the pattern of expression of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) in skin biopsies of patients with American tegumentary leishmaniasis (ATL) caused by Leishmania braziliensis. Methods: This prospective study evaluated 12 patients with ATL caused by Leishmania braziliensis confirmed by polymerase chain reaction. Immunohistochemistry was performed to determine the expression of TLR2 and TLR4. The number of NK cells, dendritic cells and macrophages in the tissue were calculated. The cytokine expression was determined using the anti-TNF-α, anti-IFN-γ, anti-IL-1 and anti-IL-6. Double immunostaining reactions were used to determine the cell expressing TLR2 and TLR4. Results: The numbers of cells expressing TLR2 and TLR4 were 145.48 ± 82.46 cell/mm 2 and 3.26 ± 4.11 cell/mm 2 respectively (p < 0.05). There was no correlation of TLR2 and TLR4 with the amount of cytokines and the number of NK cells, dendritic cells or macrophages. The double immunostaining revealed that TLR2 was expressed by macrophages. Conclusion: In human cutaneous leishmaniasis caused by Leishmania braziliensis, TLR2 is the most common TLR expressed during active disease, mainly by macrophages although without correlation with the amount of cytokines and number of cells.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Expression of TLR2 and TLR4 in lesions of patients with tegumentary american leishmaniasis

Tuon

Fernandes

Duarte

et al. 2012

Rev. Inst. Med. trop. S. Paulo

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“…Similar results were previously reported in DCs infected with L. mexicana pro-and amastigotes (Bennett et al, 2001). A possible explanation for differential responses of DCs to these two stages of parasites forms is that lipophosphoglycan (LPG), the major surface molecules on promastigotes, can activate the TLR2-mediated signaling and, further, the near absence of LPG on amastigotes is responsible for the lack of DC activation (Beverley and Turco, 1998;de Veer et al, 2003). However, it is also possible that intracellular amastigotes have evolved additional strategies to down-regulate key molecules (e.g.…”

Section: Discussionsupporting

confidence: 78%

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

Luo

Soong

2008

Molecular Immunology

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We have previously reported a link between a deficient Th1 response to Leishmania amazonensis (La) parasites and profound impairments in the cytokine/chemokine network at early stages of the infection. To define the molecular basis of these deficiencies, we focused on early and intracellular events in La-infected dendritic cells (DCs) in this study. Compared with La promastigote-infected counterparts, amastigote-infected DCs were less mature and less potent as antigen-presenting cells (APC) as evidenced by the lower expression of CD40 and CD83, suppressed cytokine expression (IL-12p40 and IL-10), reduced effectiveness for priming CD4 + T cells from naïve or infected mice. Infection with La promastigotes, but not amastigotes, triggered transient expression of IL-12p40 by DC. Both forms of parasites markedly suppressed IL-12p40, IL-12p70, and IL-6 production and increased IL-10 production when DCs were treated with LPS, IFN-γ/LPS or IFN-α/LPS as positive stimuli. Of note, pre-infection of DCs with live amastigotes resulted in multiple alterations in innate signaling pathways, including degradation of STAT2, decreased phosphorylation of STAT1, 2, 3 and ERK1/2, and markedly reduced expression of interferon regulatory factor-1 (IRF-1) and IRF-8, some of which were partially reversed by pretreatment of parasites with proteasome or protease inhibitors. The impaired IL-12 production in infected DCs was not attributed to increased IL-10 production. Together, our data suggest that La parasites, especially in their intracellular forms, have evolved unique strategies to actively downregulate early innate signaling events, resulting in impaired DC function and Th1 activation.

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“…The few TLR activators described for Leishmania are expected to be part of the extracellular products. Lipophosphoglycan (LPG) is a TLR2 agonist capable of activating mouse macrophages and human NK cells, in a MyD88-dependent manner [42–44]. Also, glycosylphosphatidylinositol, that in T. cruzi activates TLR2 and TLR4 [45–47], might be a PAMP present among Leishmania extracellular products.…”

Section: Discussionmentioning

confidence: 99%

More than just exosomes: distinct Leishmania infantum extracellular products potentiate the establishment of infection

Pérez-Cabezas

Cecílio

Silva

et al. 2018

J of Extracellular Vesicle

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The use of secretion pathways for effector molecule delivery by microorganisms is a trademark of pathogenesis. Leishmania extracellular vesicles (EVs) were shown to have significant immunomodulatory potential. Still, they will act in conjunction with other released parasite-derived products that might modify the EVs effects. Notwithstanding, the immunomodulatory properties of these non-vesicular components and their influence in the infectious process remains unknown. To address this, we explored both in vitro and in vivo the immunomodulatory potential of promastigotes extracellular material (EXO), obtained as a whole or separated in two different fractions: EVs or vesicle depleted EXO (VDE). Using an air pouch model, we observed that EVs and VDE induced a dose-dependent cell recruitment profile different from the one obtained with parasites, attracting significantly fewer neutrophils and more dendritic cells (DCs). Additionally, when we co-inoculated parasites with extracellular products a drop in cell recruitment was observed. Moreover, in vitro, while VDE (but not EVs) downregulated the expression of DCs and macrophages activation markers, both products were able to diminish the responsiveness of these cells to LPS. Finally, the presence of Leishmania infantum extracellular products in the inoculum promoted a dose-dependent infection potentiation in vivo, highlighting their relevance for the infectious process. In conclusion, our data demonstrate that EVs are not the only relevant players among the parasite exogenous products. This, together with the dose-dependency observed, opens new avenues to the comprehension of Leishmania infectious process. The approach presented here should be exploited to revisit existing data and considered for future studies in other infection models.

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MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll‐like receptor 2 signaling

Cited by 293 publications

References 53 publications

Expression of TLR2 and TLR4 in lesions of patients with tegumentary american leishmaniasis

Expression of TLR2 and TLR4 in lesions of patients with tegumentary american leishmaniasis

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

More than just exosomes: distinct Leishmania infantum extracellular products potentiate the establishment of infection

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